Antimalarial compounds and process of making them



Patented July 26, 1949 AN TIMALARIAL COMPOUNDS AND PROCESS OF MAKING THEM Robert C. Elder-field, Hastings on Hudson, and James D. Head, New York, N. Y., assignors to the United States of America as represented by the Secretary of War No Drawing. Application April 8, 1946, Serial No. 660,416

*2 Claims. (01. zoo-ass) This invention relates to certain. new antimalarials and to a process for preparing them.

. The new antimalarials are 6-methoxy-8-substi-tuted quinolines represented bythe following formula:

nN n-Nn al in which R represents a methyl or ethyl substituted tetraor penta-methylene radical, and R1 represents an alkyl radical having from 1 to 6 carbon atoms; and their salts. Thus, R may be a methyl substituted butyl radical such as lmethylbutyl, "an ethyl substituted butyl radical such as 4-ethylbutyl, amethyl substituted pentyl radical such as l-rnethylpentyl, or an ethyl sub- .stituted pentyl mama. Examples of the R1 radicals include methyl, ethyl, propyl, isopropyl, and the several butyl, pentyl, and hexy1 radicals.

These new substituted quinolines have antimalarialaction which appears to be favorable in aminoquinoline, the extra mole of the quinoline beingpresent as a buffen The mixture is held within a few degrees of45 C. for 12 to .14 hours, and the temperature is then progressively raised and finally held at 95-100" C. for 5 to 6 hours. The mixture is thenpouredinto cold water and made alkaline, as'i with sodium or potassium hydroxide solution, whichflliberates as a free base the desired 6-methoxy-8-isubstituted quinoline.

This is separated by extraction with ether; and

may be purified by extracting the ether solution with an aqueous acetic acid-sodium acetate buffer solution, and recovering the desired substituted quinoline from the "buffer solution by making it alkaline and extracting with ether. The final.

1 2 ether solution is distilled in an inert atmosphere at a pressure of less than about 1.5 mm. pressure and a bath temperature of about 225-250 0., to yield the desired free base.

The 6-methoxy-8-substituted quinolines may be characterized in the form of their oxalates. It is noted that oxalic acid does not always unite in stoichiometric ratio with the organic base, and that the characterization may be carried out by determining the percentages of base and oxalic acid in the salts, and calculating the carbon and hydrogen figures from these values. The 6- methoxy-B-substituted quinoline bases are somewhat unstable, and are desirably converted to their salts, for example the hydrohalides, the phosphates, the citrates, etc.

The following are examples of the invention:

Example 1 6-methoxy-8- (1'-methy1 4'-ethylaminobutylamino) -quinoline represented by the following may be prepared as follows: 1

1-methyl-4-ethylamin-obutyl bromide hydrobromide and certain otherfhydrobromides correspondingly used in Examples 4, 5, 6, and 7, are described by Elderfield and Brody, in their copending application Serial No; 660,413 filed April 8, 1946, now PatentNo. 2,464,199, and in the paper of Elderfield et al., J. Am. Chem. Seen, 68, pages 1579-1584 (1946).

A mixture of 275 g.of 1-methyl-4-ethylaminobutyl bromide hydrobromide, 300 m1. of warm id- C.) 1 water and 348 g. (2 mol) of (if-methoxy-fi aminoquin'oline'is'held to within a f ew degrees of 45 C., with stirring, for a period of fi -14 hours. The temperature is then increased to C. for 1 hour, thento C. for 1 hour, and finally to -100 C. for 5130 6 hours. The hot reaction mixture is then poured into 1 liter of cold water and treated with 1 liter of 40 percent potassium hydroxide solution. The resulting mixture is extracted at room temperature first with 500 ml. of ether, and then twice with 200 ml. portions ofether. The ether extracts are combined and extracted with a buffer solution prepared by. adding sodium acetateto a 0 percent solution of acetic acid until the solution is neutral or very slightly basic when tested on Congo red paper. This buffer extraction is desirably first with a 500 ml. portion, then with successively 100 ml. portions until no strong coloration of theaqu eous solution is observede The combined bufi'er extracts are then. extracted with ether, desirably in three 100 ml. portions, and

then combined with an equal volume of 40 pe r cent aqueous potassium hydroxide. Fronrthe resulting aqueous solution[the substituted,quinc line base is removed by extraction with ether, desirably successively with a 39;) ml. portionand two 100 ml. portions, the cambinedether extracts are dried as over magnesium-sulfate, and'fih tered. The ether extract is then concentrated on a steam bath, arid the residueds distilled, first at a temperature of about 150 C;- under. I

partial vacuum, and then at a pressure oi less than 0.5 mm. in an inert atmosphere-such as nitrogen. This yields the desired 6-methoxy- 8- hy l ethylaminobutylaminot-quinoline, which bijils. at.f 9.-9?* at 0,4. mm. pressure. It formsan oxalate melting at. 175-173 C.

1 Example 2; e ho yr 3 1-m th l-1 isp opy w p r n -qu o1 n tr r s nted b t llowing formula r :\N j

ss re liea eeese on. ,1 one 1 may be prepared by the procedure o f Example 1,

save that instead of 1 mEthyll-ethylaminobutyl bromide hydrobromide. the hydrobromide of 1- methyl-5-isopropylaminopentyl I bromide, is used. This latter may be prepared as follows; Thesodium derivative of acetoaceti'c ester is reacted with trimethylene bromide and the resulting condensation product is subjectedto ketonic hydrolysis to obtain 1-br0mohexanone-5. ,This hexanone is reduced to the corresponding hexanol by reduction' with aluminum isopropoxide in isopropanol solution. The. hexanolthusobtained is reacted with isopropylamine for about 6 days at room temperature, to obtain 1-(Nisopropy1amino)- hexanol-5. This aminohexanolis converted to l-methyl-5-isopropylaminopentyl .bromide hydrobromide by treating a cold. benzenesolution of the aminohexanol with .thionyl'. bromide. The 1-methyl-5eisopropylaminopentyl bromide hydrohromide. precipitates .as: a. solid,,-,which. after recrystallization fromamnixture oft acetona and ether melts at 142-14311: C.

E mpl 31;.

6-methoxy-8-(4'-ethyl 41 ethylaminobutylamino) -qu1'noline representedby the following formula 7 may be preparedby the procedure of Example 1,

save that instead of the hydrobromide there used, the hydrobromide of. sir-ethyl.-4=ethy1aminobutyl '4 No. 660,413, and in the Elderfield et a1. publication J. Am. Chem. Soc., 68, pages 1579-1584 (1946). V

The 6-methoxy-8-(4-=ethyl-4'-ethy1amin0bu tylamino)-quinoline boilsat 167-169 .C. at 0.1 mm. pressure, and forms. a mono-oxalate which melts at 184-186? C.

7 Example 4 i 6-methoxye8 -(l'emethyl 4 n-propylaminov butylamino)-quinoline may be prepared by the procedure of Example 1, save that instead of the hydrobromide there used, l-metnyli-n-propylaminobutyl bromide hydrobromide is used. This latter compound is disclosed by;E1derfieId and Brody, supra.

The 6-methoxy-8-(l -methyl-'-n propylaminobutylamino)rquinoline boils at 175-178 C. at 0.2 mm.v pressure. It formsan oxalate melting at 165-167? C. e

. Example 6.

6-methoxy-8-(l methyl'- 4' isobutylaminobutylaminohquinoline may be prepared by the procedure .of Example 1, save: that instead of the hydrobromide there used, l-methyl--isobutylaminobutyl bromide hydrobromide is used. This lattericompound is disclosed by Elderfield and Brody, supra.

The fifmethoxyefi- 1'-methy1-4 isobutylaminobutylaminm-quinoline boils at ISO-184 C. at

" 0.3 mm. pr essure. It forms an oxalate melting abide-173C; I i I Example? 1 f 6-methoxy-8-(1.-methyl 4" tert.butylaminobutylamino) -quino1inemaybe-prepared by the procedure of Example 1,, save that instead. of the hydrobromide there used, -1-meth;yl-4-tert.butylaminobutyl bromide hydrobromide is used. This latter compound is disclosed by Elderfield and Brody supra.

The G-methoxy-S-(Y-methyl 4' tert.butylaminobutylamino)-quinoline boils at 180185 C.

at 0.3 mm. pressure. It forms an oxalate melting at MiG-145 'C.

. Example. 8 7 Any of the preceding examples may be repeated,

save that hydrobromides of other alkylaminoalkyl bromide is used. This lattercompound. is described in the said copendingapplication- Serial bromides of Formula 2 are used, to produce other S-methoxy-S-substituted quinolines of- Formula 1, and their saltsli We claimasour invention: 7 a 1. The new antimalarials of theclass consisting of 6-methoxy-8-substituted quinolines' represented by the following formula in which R is a polymethylene chain including a lower alkyl side chain and having from 4 to 5 carbon atoms, the said side chain being one of the radicals selected from the group consisting of methyl and ethyl, and R1 is an alkyl radical having from 1 to 6 carbon atoms, and their salts.

2. The new antimalarials of the class consisting of fi-methoxy-B-substituted quinolines represented by the following formula in which R1 is an alkyl radical having from 1 to 6 carbon atoms, and their salts. 3. The new antimalarials of the class consisting of 6-methoxy-8-substituted quinolines represented by the following formula in which R1 is an alkyl radical having from 1 to 6 carbon atoms, and their salts.

4. The new antimalarials of the class consisting of G-methoxy-S-substituted quinolines represented by the following formula HNCH(OHz)4-NHR,

in whicn R1 is an alkyl radical having from 1 to 6 carbon atoms, and their salts.

5. The process of preparing the new antimalarials having the formula N HN-R-NH-Bi defined in claim 1 which comprises condensing 6-methoxy-8-aminoquino1ine and the hydrobromide of an alkylaminoalkyl bromide of the following formula Br--Rr-NH--R1 in which R and R1 have the same meaning as in claim 1.

6. The process of preparing the new antimalarials having the formula HNRNHR1 defined in claim 1 which comprises condensing 6--meth0Xy-8-amin0quin0line and the hydrobromide of an alkylaminoalkyl bromide of the following formula Br-R-NI-IR1 in which R and R1 have the same meaning as in claim 1 in aqueous solution and in the presence of an extra molecular portion of 6-methoxy-8- aminoquinoline as a buffer.

7. The process of preparing the new antimalarials having the formula N HN-R-NH-Ri defined in claim 1 which comprises mixing G-methoxy-B-aminoquinoline and the hydrobro- REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,938,047 Schonhofer Dec. 5, 1938 FOREIGN PATENTS Number Country Date 486,079 Germany Dec. 2, 1929 OTHER REFERENCES Shriner and Upson, Synthetic Antimalarials (published in Bloomington, Indiana, 1941), page 9. (Copy in Div. 59). 

